Regulation of Liver Metabolism by the Endosomal GTPase Rab5
In this study we uncovered a novel requirement of Rab5 and the endosomal system for the regulation of hepatic metabolism that goes beyond the classical view of controlling surface expression of nutrient transporters. Using a combinational omics approach we found that depletion of Rab5 in the liver phenocopied a glycogen storage disease, called von Gierke’s disease, characterized by hypoglycemia, hepatomegaly, hypercholesterolemia, hyperlipidemia and glycogen accumulation. These phenotypes were due to a dramatic reduction in Glucose-6-Phosphatase (G6Pase) similar to von Gierke’s disease. Interestingly, we uncovered functional alterations in the transcription factors, which regulate G6Pase expression, suggesting that Rab5 and/or endosomes are required for the gluconeogenic transcription program. Our data highlight a novel requirement of Rab5 and the endosomal system for the regulation of hepatic glucose metabolism that has important implications for metabolic diseases. This was a collaborative study of several groups of the Virtual Liver Network (www.virtual-liver.de): Hergo Holzhütter; modeling, Matthias Mann; proteomics, Agapios Sachinidis; transcriptomics, Andrej Shevchenko; lipidomics, Marino Zerial; cell biology). Read more about this study here.